Evidence for increased tumor incidence in NKG2D-deficient mice has set NKG2D as the first innate immune receptor implicated in immunosurveillance of tumors. In this viewpoint article, we discuss recent genetic insight into NKG2D-mediated suppression of spontaneous tumor development in the context of NKG2D signaling properties. Moreover, we identify unresolved issues and consider how an understanding of NKG2D-receptor and -ligand biology can facilitate successful therapeutic intervention of human cancer.